HSP90 beta regulates rapsyn turnover and subsequent AChR cluster formation and maintenance.
Rapsyn, an acetylcholine receptor (AChR)-interacting protein, is essential for synapse formation at the neuromuscular junction (NMJ). Like many synaptic proteins, rapsyn turns over rapidly at synapses. However, little is known about molecular mechanisms that govern rapsyn stability. Using a differential mass-spectrometry approach, we identified heat-shock protein 90beta (HSP90beta) as a component in surface AChR clusters. The HSP90beta-AChR interaction required rapsyn and was stimulated by agrin. Inhibition of HSP90beta activity or expression, or disruption of its interaction with rapsyn attenuated agrin-induced formation of AChR clusters in vitro and impaired the development and maintenance of the NMJ in vivo. Finally, we showed that HSP90beta was necessary for rapsyn stabilization and regulated its proteasome-dependent degradation. Together, these results indicate a role of HSP90beta in NMJ development by regulating rapsyn turnover and subsequent AChR cluster formation and maintenance.
Luo
Shiwen
S
Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Zhang
Bin
B
Dong
Xian-Ping
XP
Tao
Yanmei
Y
Ting
Annie
A
Zhou
Zheng
Z
Meixiong
James
J
Luo
Junjie
J
Chiu
F C Alex
FC
Xiong
Wen C
WC
Mei
Lin
L
D000818:Animals; D002460:Cell Line; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism* / Q000502:physiology; D032446:Myoblasts / Q000502:physiology; D011247:Pregnancy; D011940:Receptor Aggregation / Q000235:genetics; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D035683:MicroRNAs; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; C051609:peripheral membrane protein 43K